In 1926, British wizard and magizoologist Newton Scamander arrives in New York City with a suitcase full of magical creatures. His intention is to continue his global research and rescue of magical creatures, documenting them for his eventual textbook. However, some of his creatures escape from the suitcase, causing trouble for both the wizarding and No-Maj (non-magical) worlds. Newt soon crosses paths with Tina Goldstein, a demoted Auror from the Magical Congress of the United States of America (MACUSA), who becomes aware of his unauthorized activities.

As Newt struggles to recapture his lost beasts, he and Tina are inadvertently assisted by No-Maj cannery worker Jacob Kowalski, who has ambitions of opening his own bakery. Jacob is inadvertently exposed to the magical world when some creatures escape from Newt's enchanted suitcase. The unlikely trio is completed by Tina's sister, Queenie, a legilimens who can read minds. The group becomes embroiled in a larger conflict when the American wizarding authority, MACUSA, is on high alert due to the threat of exposure by a dark force terrorizing New York, coincidentally coinciding with Newt's visit. This dark presence has been causing mysterious destruction around the city, which the group must confront while facing their own personal challenges and the societal tensions between magical and non-magical communities.